Suicide of a Cancer Cell

23. November 2007

The tumor suppressor factor p53 prevents the unchecked reproduction of cells but often is modified and ineffective in tumor patients. p73, a close relative, could be the more rewarding target of novel strategies against cancer cells.

The “tumor-suppressor factor”, baptized p53 by cancer researchers, is considered the “guardian of thegenome”. It appears if the cell is under stress. Perhaps rays have damaged theDNA or aggressive radicals have started an attack on the genetic material. p53takes care of it that the cells do not proliferate any further until the damagehas been repaired.

Presumably the factor makessure as well that the cell differentiates instead of seeing to offspring. Inserious cases, the cell commits suicide to avoid further damage to the tissue.

About 10 years ago morefamily members of this transcription factor appeared in publications: p63 andp73. Both have similar but not identical functions to their famous relative.While p53 often looses its function in tumor cells because of mutations, p73hardly ever changes. To drive those cells into apoptosis, theprogrammed cell-suicide, more and more oncological researchers are interestedin p73.

Peptide against tumor suppressor-repression

The working group of KevinRyan at the Beatson Institute for Cancer Research in Glasgow has discovered a potentialAchilles' heel of the tumor. The details were published in April this year inthe Journal of Clinical Investigation . A synthetic peptide (37AA),37 amino acids long and originating from p53, induces apoptosis in numeroustumor cell lines, completely independent from having a functioning p53 gene. Thepeptide piece does not directly activate the according signal routes for thesuicide program though, it inactivates an inhibitor. The cell ready to splitnormally suppresses the activity of the p53 family members with it. In cellsnot having a functioning p53, the p73 will become operative. As a deputy forthe big brother so to speak, it causes the nemesis of the cell out of control.

The principle not onlyworks in cell cultures but also in mice. The researchers let the coloncarcinoma cell LoVo grow in mice and treated it then with nano-particles madefrom polypropylene-DNA complexes coding for the 37AA peptide. Independent fromthe expression of p53, the tumor regressed. For Kevin Ryan the results open achance for new cancer therapies: “At first we thought, p73 was just a ‘sleepingpartner' of p53. As a matter of fact we might be able to use its function forcancer treatment. Even though our studies are at a very early stage, we plan todevelop an agent similar to 37AA which can be tested on human tumors”.

Jobsharing for p53 and p73

For years, a Germanresearch team is concentrating on p53 and its relatives as well: Just lastyear, at the Rudolf-Virchow-Zentrum für Experimentelle Biomedizin inWürzburg, Thorsten Stiewe and his team verified the meaning of p73 and p63 on a model of musclecells. P53 and p73 shared the job tin order to stop an uncontrolled proliferation.While p53 took care of the synthesis of the tumor suppressor factor Rb (=Retinoblastoma-protein), p63 and p73 saw to its permanent activation. A body'sown antagonist blocks thefunction of p53 & Co. and might be suitable as an objective for innovativetherapies. ∆Np73, in co-operation with other oncogenes, enables thetransformations of myoblasts to tumor cells. In rhabdomyosarcomes, i. e. tumorsin the skeletal muscles, this factor is abundant in high concentration.

As Thorsten Stiewe emphasizes, those new approaches do not go beyond the labyet. “But since tumor cells quite often do not have a functioning tumorsuppressor protein p53, the results with p73 are really interesting”. Thefurther road to the agent should not be quite simple because the gene therapeuticmethods as described by researchers in Glasgow about laboratory mice, do notreach all tumor cells, explains the head of the Würzburg department formolecular tumor biology. A small synthetic molecule would have better chanceshere to reach the cell and stop the cell cycle there together with p53and its relatives. Although p53 is known for nearly 30 years and worked on alot, there is no working drug supporting its functions and stopping the tumorfrom growing. Perhaps the unknown “big brother” is the better target.

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